Newly found protein helps cells build tissues

Date:

April 2, 2012

Source:

Brown University

Summary:

Biologists have found a new molecule in fruit flies that is key to the information exchange needed to build wings properly. They have also uncovered evidence that an analogous protein may exist in people and may be associated with problems such as cleft lip, or premature ovarian failure.

Brown University biologists have found a new molecule in fruit flies that is key to the information exchange needed to build wings properly. They have also uncovered evidence that an analogous protein may exist in people and may be associated with problems such as cleft lip, or premature ovarian failure.

As they work together to form body parts, cells in developing organisms communicate like workers at a construction site. The discovery of a new signaling molecule in flies by Brown University biologists not only helps explain how cells send many long-haul messages, but also provides new clues for researchers who study how human development goes awry, for instance in cases of cleft lip and palate.

For all the diversity of life, animal cells employ only a small set of proteins to send those jobsite signals that coordinate construction. For that reason, said Kristi Wharton, associate professor of molecular biology, cell biology and biochemistry, studying these proteins and pathways in fruit flies can allow biologists and physicians to explain how development and other cellular processes occur in a wide variety of creatures and tissues.

"We are interested in how the pattern of a hand forms or how the pattern of a wing forms," Wharton said. "How do cells know their position in a developing tissue?"

In humans a key family of the signaling molecules that convey such messages are bone morphogenic proteins (BMPs). In fruit flies the directly analagous proteins carry the name "glass-bottom boat" (Gbb), because a mutant form makes larvae appear clear instead of milky white. To date, the conventional wisdom has been that signaling comes from a fly form of BMP known as Gbb15.

"The thought for the longest time is that this smaller protein is the only product that is formed and important for signaling," Wharton said. "But we found another form of this signaling molecule that was not previously known."

Wharton and former postdoctoral fellow Takuya Akiyama introduce the new molecule, Gbb38, in the April 3 edition of the journal Science Signaling. Experiments showed that in tissues where it was abundant, particularly parts of the wing, Gbb38 proved responsible for more signaling activity than Gbb15, and appeared especially important for carrying long-haul signals.

Possible links to humans

In addition to the findings in flies, Akiyama found that mutations in the genes for making BMPs in humans that directly mirror the genetic code for making Gbb38 in flies, occur in people with cleft lip (with or without cleft palate), and the reproductive disorders premature ovarian failure and persistent Mullerian duct syndrome. In other words, a mutation that interrupts Gbb38 production in flies, is analogous to the mutations associated with developmental disorders in different tissues in people.

The genetic analysis doesn't prove that mutations that hinder the production of an analogous signaling protein in humans would be the cause of those diseases, Wharton said. In fact, a longer-form BMP like Gbb38 has yet to be discovered in people. But the new discovery at least suggests the need for research to investigate that link, perhaps first in mice, she said.

Another potential benefit of the finding, she said, is that finding a Gbb38 analogue in humans could improve the current use of BMPs as therapeutics for bone repair, spinal fusions, and reconstruction of maxillofacial bone defects.

"If large forms of human BMPs are indeed present, which is suggested by the three human mutations, then they could be a very useful alternatives to the short BMPs because the large forms are more active in terms of signaling and have different properties in vivo," Wharton said.

Discovery on the wing

In the new paper, aided by an antibody provided by second author Guillermo Marques of the University of Alabama, Akiyama and Wharton were able to discover Gbb38 because they first asked what happened when they interrupted the creation of Gbb15. When they did that, by mutating the genetic instructions that tell enzymes where to cut Gbb15 out of a longer protein, they noticed that signaling activity was only mildly reduced instead of completely gone as conventional wisdom would have predicted.

Further research showed that there was another place where enzymes could cut to make a protein. Cutting at that spot yielded the longer Gbb38 protein. When they interrupted that cleavage in flies, the researchers found that signaling was significantly hindered. A total reduction in signaling came from interrupting both Gbb15 and Gbb38.

In local areas of wing tissue, meanwhile, Akiyama found that interrupting Gbb15 had consequences for signaling only among neighboring cells. Interrupting Gbb38, meanwhile, left local signaling intact, but created problems significantly farther away.

"The small protein doesn't move very far across the tissue," Wharton said. "But we found the large protein has a very long range. That may provide one answer to the long-standing question about what regulates the range of these signaling molecules."

The view for developmental biologists, therefore, may indeed be clearer in a larger glass-bottom boat.

The National Institute of General Medical Sciences funded the research.

Story Source:

The above post is reprinted from materials provided by Brown University. Note: Materials may be edited for content and length.

July 31, 2015  Resettlement projects in the Amazon are driving severe tropical deforestation, according to new research. Widely hailed as a socially responsible and 'innocuous' strategy of land redistribution, ... read more

July 29, 2015  Viewing aquarium displays led to noticeable reductions in blood pressure and heart rate, a research team found in the first study of its kind. They also noted that higher numbers of fish helped to ... read more

July 31, 2015  A new study examines how consuming the concentrated extract of thylakoids found in spinach can reduce hunger and cravings. Thylakoids encourage the release of satiety hormones, which is very ... read more

July 30, 2015  The behavior of fruit flies, which are commonly used in laboratory experiments, is altered by electric fields, new research shows. The research indicates that the wings of the insects are disturbed ... read more

July 31, 2015  Starvation early in life can alter an organism for generations to come, according to a new study in nematodes. The epigenetic effects are a 'bet-hedging strategy.' Famine survivors are smaller and ... read more

July 31, 2015  The humble butterfly could hold the key to unlocking new techniques to make solar energy cheaper and more efficient, pioneering new research has shown. By mimicking the v-shaped posture adopted by ... read more

Oct. 22, 2014  Bright colors appear on a fruit fly’s transparent wings against a dark background as a result of light refraction. Researchers have now demonstrated that females choose a mate based on the males’ ... read more

Oct. 19, 2014  Scientists studying birth defects in humans and purebred dogs have identified an association between cleft lip and cleft palate -- conditions that occur when the lip and mouth fail to form properly ... read more

May 26, 2014  A specific stretch of DNA controls far-off genes to influence the formation of the face, researchers have found. The new study, outlining how this is done, helps understand the genetic causes of ... read more

Jan. 26, 2012  HIV-positive mothers have been able to guard against transmitting the disease to their babies by taking antiretroviral drugs during pregnancy. Although the drugs prevent children from being born with ... read more